KR101399916B1 - Process for production of carboxylic acid chloride compound - Google Patents

Process for production of carboxylic acid chloride compound Download PDF

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KR101399916B1
KR101399916B1 KR1020087023770A KR20087023770A KR101399916B1 KR 101399916 B1 KR101399916 B1 KR 101399916B1 KR 1020087023770 A KR1020087023770 A KR 1020087023770A KR 20087023770 A KR20087023770 A KR 20087023770A KR 101399916 B1 KR101399916 B1 KR 101399916B1
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carboxylic acid
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KR20080114771A (en
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다쓰야 이시카와
쇼우이치 콘도우
사토지 다카하시
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아지노모토 가부시키가이샤
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00Preparation of carboxylic acid amides
    • C07C231/02Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07BGENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B53/00Asymmetric syntheses
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/58Preparation of carboxylic acid halides
    • C07C51/60Preparation of carboxylic acid halides by conversion of carboxylic acids or their anhydrides or esters, lactones, salts into halides with the same carboxylic acid part
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00Systems containing only non-condensed rings
    • C07C2601/12Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14The ring being saturated

Abstract

The present invention relates to a process for preparing a carboxylic acid chloride compound of formula (III), characterized in that the carboxylic acid compound of formula (I) is reacted with an acid chlorinating agent in the presence of a urea compound of formula (II). This method can produce a carboxylic acid chloride compound at high purity or at a high yield. The carboxylic acid chloride compound prepared by this method is useful as an intermediate for the preparation of a D-phenylalanine derivative used as a diabetes remedy.
Formula I
Figure 112013110703448-pct00019
(II)
Figure 112013110703448-pct00020
(III)
Figure 112013110703448-pct00021
In the above formulas I, II and III,
Ring A is a cyclohexane ring or a benzene ring,
R 1 is an alkyl group having 1 to 6 carbon atoms,
R 2 to R 6 are each independently a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, and R 5 and R 6 may be bonded to each other. In this case, -R 5 -R 6 - is an ethylene group or the like
Carboxylic acid chloride, trans-4-isopropylcyclohexanecarbonyl chloride, ICCC

Description

The present invention relates to a process for producing a carboxylic acid chloride compound,

The present invention relates to a process for preparing a carboxylic acid chloride compound having a hypoglycemic effect and serving as an intermediate for the preparation of a D-phenylalanine derivative used as a therapeutic agent for diabetes, and a process for producing a D-phenylalanine derivative using the carboxylic acid chloride compound.

D-phenylalanine derivatives containing N- (trans-4-isopropylcyclohexylcarbonyl) -D-phenylalanine (nateglinide) have a hypoglycemic effect and are already described in Patent Document 1 as useful as a diabetes remedy.

Patent Document 2 discloses a method for synthesizing phenylalanine derivatives, which includes Schotten-Baumann method for reacting trans-4-isopropylcyclohexanecarbonyl chloride (hereinafter ICCC) with phenylalanine (Phe) And the tetraglycan can be synthesized as follows.

Figure 112008068151665-pct00001

Namely, the carboxylic acid chloride containing ICCC is useful as a production intermediate of D-phenylalanine derivatives useful as a diabetes remedy.

Various methods for synthesizing trans-4-isopropylcyclohexanecarbonyl chloride (ICCC), which is used as a starting material for synthesizing the nateglinide, have been known, but Patent Document 3 discloses a method of synthesizing trans-4-isopropylcyclohexanecarboxylic acid Hereinafter, ICC) can be exemplified by the following methods for operating phosphorus chloride such as phosphorus trichloride and phosphorus trichloride or thionyl chloride.

Figure 112008068151665-pct00002

However, there is still a need for a method for preparing a carboxylic acid chloride compound that includes ICCC, for example, a faster reaction rate, higher product purity, and higher yield.

Patent Document 1: Japanese Patent Publication No. 4-15221

Patent Document 2: International Publication No. WO 02/32853

Patent Document 3: JP-A-7-17899

It is an object of the present invention to provide a process for producing a carboxylic acid chloride compound at high purity or at a high yield.

It is another object of the present invention to provide a method for efficiently producing a D-phenylalanine derivative such as nateglinide through a process for producing a carboxylic acid chloride compound.

DISCLOSURE OF THE INVENTION The present inventors have made extensive studies in order to achieve the above object and found that when the reaction of an acid chloride reagent such as thionyl chloride and a carboxylic acid compound is carried out in the presence of a compound having a specific urea structure, The present invention has been accomplished on the basis of the finding that the above problems can be solved.

That is, the present invention provides a process for preparing a carboxylic acid chloride compound of formula (III), characterized in that the carboxylic acid compound of formula (I) is reacted with an acid chlorinating agent in the presence of a urea compound of formula (II).

Figure 112008068151665-pct00003

Figure 112008068151665-pct00004

Figure 112008068151665-pct00005

In the above formulas I, II and III,

Ring A is a cyclohexane ring or a benzene ring,

R 1 is an alkyl group having 1 to 6 carbon atoms,

R 2 , R 3 , R 5 and R 6 are each independently a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, or R 5 and R 6 may be bonded to each other. In this case, -R 5 -R 6 - , Trimethylene group or tetramethylene group.

The present invention also provides a process for producing a D-phenylalanine derivative of the formula (V), which comprises reacting a D-phenylalanine compound of the formula (IV) with a carboxylic acid chloride compound of the formula (III) to provide.

(III)

Figure 112008068151665-pct00006

Figure 112008068151665-pct00007

Figure 112008068151665-pct00008

In the above formulas (III), (IV) and (V)

Ring A is a cyclohexane ring or a benzene ring,

R 1 is an alkyl group having 1 to 6 carbon atoms,

R 4 is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms or a benzyl group.

According to the present invention, since the reaction proceeds rapidly by using a specific urea compound, the desired acid chloride compound can be rapidly obtained.

Further, according to a preferred embodiment of the present invention, even when the carboxylic acid compound is solid, since it becomes a liquid phase quickly after the initiation of the reaction and the stirring operation and the like become easy, there is an advantage that the reaction can be easily controlled. In addition, when thionyl chloride is used as the acid chloride reagent, it can be suppressed to a small amount, which is economical, good in environment, and easy to remove thionyl chloride by distillation. In addition, the acid chloride compound obtained by the present invention has less impurities such as geometric isomers.

BEST MODE FOR CARRYING OUT THE INVENTION [

In the carboxylic acid compound of formula (I) used in the present invention, ring A is a cyclohexane ring or a benzene ring, but cyclohexane ring is preferred. R 1 is a linear or branched alkyl group having 1 to 6 carbon atoms, preferably an alkyl group having 2 to 5 carbon atoms, more preferably a branched alkyl group having 3 to 5 carbon atoms, and most preferably an isopropyl group. R 1 may be any of the o-, m- or p-positions for the carboxyl group, but is preferably in the p-position. The most preferred carboxylic acid compound of formula (I) is trans-4-isopropyl-cyclohexanecarboxylic acid.

In the present invention, a urea compound of the formula (II) is used as a catalyst in the reaction of the carboxylic acid compound of the formula (I) with an acid chlorinating agent such as thionyl chloride. The urea compound of the formula (II) includes urea itself, dialkylurea, trialkyl urea, tetraalkyl urea and the like, and tetraalkylurea is preferable. In particular, in formula (II), R 2 , R 3 , R 5 and R 6 independently of one another are an alkyl group having 1 to 3 carbon atoms or R 5 and R 6 may be bonded to each other. In this case, -R 5 -R 6 - An ethylene group, a trimethylene group, or a tetramethylene group. In particular, in formula II, R 5 and R 6 are bonded to -R 5 -R 6 - all the ethylene group and 1,3-dialkyl-2-imidazolidinone di discussed using a preferred, R 2 and R 3 is It is further preferable to use 1,3-dimethyl-2-imidazolidinone (DMI) which is a methyl group. Since DMI is relatively stable in strong acids, has thermal stability, and is difficult to generate decomposed products, it is preferable not only in terms of catalytic activity but also in terms of impurity control. In the formula (II), R 2 and R 3 are both hydrogen atoms or methyl groups, and R 5 and R 6 are both hydrogen atoms, or R 2 , R 3 , R 5 and R 6 are all methyl groups.

The acid chloridating agent to be used in the present invention includes at least one acid chloridating agent selected from the group consisting of thionyl chloride, oxalyl chloride, phosgene, phosphorus trichloride, phosphorus trichloride and phosphorous chloride, Thionyl chloride.

When the acid chloridating agent is thionyl chloride, 0.8 to 5 mol of thionyl chloride is industrially preferably used, more preferably 0.8 to 2 mol, and most preferably 1 to 3 mol, relative to 1 mol of the carboxylic acid compound of formula (I) It is preferable to use 1.2 moles. The urea compound of the formula (II) is preferably used in a catalytic amount. For example, it is preferably 0.001 to 5 parts by weight, more preferably 0.01 to 3 parts by weight, per 100 parts by weight of the carboxylic acid compound of the formula (I) 0.01 to 1 part by weight is used. However, the urea compound may be used in a larger amount and used as a solvent.

The acid chloride is preferably solventless, but a solvent may also be used. The reaction is preferably carried out at a temperature of about room temperature to about 80 캜, and more preferably from 30 to 60 캜. The reaction is preferably carried out under atmospheric pressure. After completion of the reaction, it is preferable to distill off the acidic gas such as dissolved sulfur dioxide and chlorine gas in the reaction solution under reduced pressure, and distilling off the unreacted thionyl chloride desirable.

The acid chlorinating agent such as oxalyl chloride, phosgene, phosphorus pentachloride, phosphorus trichloride, phosphorus chloride and the like can be used in the present invention in the same manner as in the case of thionyl chloride.

In the present invention, the carboxylic acid chloride compound of formula (III) is most preferably trans-4-isopropyl-cyclohexanecarbonyl chloride.

A D-phenylalanine derivative of the formula (V) can be prepared by preparing a carboxylic acid chloride compound of the formula (III) by the above production method and conducting the conversion. More specifically, nateglinide can be produced by preparing ICCC by the above production method and then performing conversion.

In the present invention, a D-phenylalanine derivative of the formula (V) is prepared by reacting a D-phenylalanine compound of the formula (IV) using the Schottenbaumann reaction after preparing a carboxylic acid chloride compound of the formula (III) In formula (IV), R < 4 > is preferably a hydrogen atom. A D-phenylalanine derivative of the formula (V) is most preferably a nateglinide.

The above reaction is preferably carried out according to the conditions described in Patent Document 2 (WO02 / 32853). The content of Patent Document 2 is included in the description of this specification.

Specifically, the acid chloride compound of formula (III) and the phenylalanine compound of formula (IV) are preferably reacted with potassium hydroxide in a mixed solvent of an organic solvent and water while maintaining the alkaline conditions. The pH of the mixed solvent is preferably 12.5 or more, More preferably, the reaction may be carried out while maintaining the alkali condition at pH 13.5 or more. However, when the pH exceeds 14, the reaction liquid may be colored, so it is necessary to be careful when it is desired to avoid coloring. When the pH is adjusted, it may be out of the above-mentioned range, but if it is temporary, there is no problem because it does not adversely affect it. In addition, the value of the pH here is indicated by the value of a pH meter using a glass electrode. The concentration of the aqueous potassium hydroxide solution is not particularly limited, but is usually 2 to 50% by weight, preferably 5 to 25% by weight.

As the organic solvent, it is mixed with water. Specific examples thereof include acetone, methyl ethyl ketone, dioxane, tetrahydrofuran, acetonitrile, methanol, ethanol, propanol and isopropanol.

The mixing ratio of the organic solvent and water differs depending on the acid chloride used and can not be uniformly defined, but is 10:90 to 80:20, preferably 15:85 to 40:60.

Although the temperature and the concentration of the reaction are not uniformly defined because they differ depending on the acid chloride and the reaction solvent to be used, the reaction temperature is usually -5 to 25 ° C, preferably 0 to 15 ° C, Is usually 1 to 20% by weight, preferably 2 to 10% by weight. Here, appropriate conditions can be determined in terms of yield, operability, and productivity.

As a reaction method, for example, a phenylalanine compound is dissolved in water by using an almost equimolar amount of an aqueous solution of potassium hydroxide, an organic solvent is added, and further an aqueous potassium hydroxide solution is added to adjust the pH, and the acid chloride compound is added dropwise May be adopted. The dropping time is preferably about 15 minutes to 2 hours. The molar ratio of the phenyl chloride compound used in the reaction to the acid chloride compound such as trans-4-isopropylcyclohexylcarbonyl chloride is preferably 0.5: 1 to 2: 1, preferably 0.9: 1 to 1.5: 1 . In the reaction of the phenylalanine compound and the acid chloride compound such as trans-4-isopropylcyclohexylcarbonyl chloride, the concentration is 2% by weight to 15% by weight in terms of phenylalanine compound concentration, desirable. The resulting acylphenylalanine derivative can be obtained by precipitating crystals by acidifying the reaction solution with hydrochloric acid or the like, and obtaining the crystals by filtration and washing with water.

According to such a production method, it is possible to easily produce D-phenylalanine derivatives such as natiglinide of high purity by using the Schottenbaummann reaction, which is an industrially superior reaction.

In addition, when a carboxylic acid chloride compound of formula (III) is prepared and then converted to obtain a D-phenylalanine derivative of formula (V) wherein R 4 is an alkyl group having 1 to 3 carbon atoms or a benzyl group, A D-phenylalanine derivative of the formula V-2 can be obtained.

[ Formula V-2 ]

Figure 112008068151665-pct00009

In the above formula (V-2)

Ring A is a cyclohexane ring or a benzene ring,

R 1 is an alkyl group having 1 to 6 carbon atoms.

The de-esterification reaction may, for example, be hydrolysis carried out in the presence of an acid or an alkali, if necessary. When R 4 is a benzyl group, a catalytic hydrogenation reaction may also be mentioned.

The present invention will be described with reference to the following examples.

Example 1 (using 2 wt% of DMI)

0.61 g (2%) of 1,3-dimethyl-2-imidazolidinone (DMI) was added to 30 g (176 mmol) of trans-4-isopropylcyclohexanecarboxylic acid (ICC) and 21.6 g of thionyl chloride 183 mmol, 1.03 eq.) Was added dropwise over 3 hours (ICC at the end of the drop was 1.1% remained). After the dropwise addition, the reaction was continued for 1 hour (ICC was 0.4% and thionyl chloride was 0.49% by weight) while distilling off the dissolved acid gas (sulfur dioxide and hydrogen chloride) at 30 kPa and 40 ° C under reduced pressure. Further, 33.6 g (content: 96.8% by weight) of trans-4-isopropylcyclohexanecarbonyl chloride (ICCC) was obtained as a concentrated residue by performing distillation of thionyl chloride at 5 kPa and 40 ° C for 3 hours. The ICC remaining in the ICCC was 0.3%, and the thionyl chloride was less than 0.01% by weight.

Example 2 (using 0.05 wt% of DMI)

0.014 g (0.05% by weight) of DMI was added to 30 g (176 mmol) of ICC, and 21.6 g (182 mmol, 1.03 equivalent) of thionyl chloride was added dropwise at 40 캜 for 3 hours (ICC at the end of dropwise addition was 5.1%). After the dropwise addition, the reaction was continued for 1 hour (ICC of 1.5% and thionyl chloride of 0.33% by weight) while distilling off the dissolved acidic gas at 30 kPa and 40 ° C under reduced pressure. Further, distillation of thionyl chloride at 5 kPa and 40 占 폚 was carried out for 3 hours to obtain 32.9 g (content: 98.5 wt%) of ICCC as a concentrated residue. The amount of ICC remaining in the ICCC was 1.3%, and the content of thionyl chloride was 0.13% by weight.

Comparative Example 1 (DMI not used)

21.6 g (182 mmol, 1.03 equivalent) of thionyl chloride was added dropwise to 30 g (176 mmol) of ICC at 40 占 폚 for 3 hours (ICC at the end of the dropping was 31.7%). After the dropwise addition, the reaction was continued for 1 hour (ICC remained 18.9%) while distilling off the dissolved acidic gas at 30 kPa and 40 ° C under reduced pressure. Further, distillation of thionyl chloride at 5 kPa, 40 캜 was carried out for 3 hours, and 32.6 g of concentrated residue containing ICCC (content 88.3%) was obtained. The ICC remaining in the concentrated residue was 12.1%, and thionyl chloride was 0.39% by weight.

By comparing the results of Example 1 and the results of Comparative Example 1, it was confirmed that the amount of thionyl chloride in the case of not using DMI (Comparative Example 1) and the case of using DMI (Example 1) .

Comparative Example 2 (not using DMI, 1.5 equivalents of thionyl chloride)

31.5 g (265 mmol, 1.5 eq.) Of thionyl chloride was added dropwise to 30 g (176 mmol) of ICC at 40 占 폚 for 3 hours (ICC at the end of dropwise addition was 15.0%). After the dropwise addition, the reaction was continued for 4 hours (ICC was 3.9% for 1 hour, 1.6% for 4 hours) while distilling off the dissolved acid gas at 30 kPa and 40 ° C. Then, thionyl chloride was distilled off at 5 kPa and 40 DEG C for 3 hours. The ICC remaining in the residue containing ICCC at the time point was 1.6%, and thionyl chloride was 9.7% by weight.

Based on the above facts, ICCC uses 1.5 equivalents of thionyl chloride, so that the residual ICC becomes 2.0% or less and becomes usable. However, it was found that the residual amount of thionyl chloride was as large as 9.7% by weight, and even when DMI was used, it was not reached to 0.2% by weight or less which can be used under the same conditions.

Thus, thionyl chloride was distilled off at 5 kPa and 40 ° C for 7 hours to obtain 33.4 g of a concentrated residue containing ICCC, but the remaining ICC in this ICCC was 1.4% and thionyl chloride was 2.0% by weight . In other words, when DMI is not used, it can be seen that even when thionyl chloride is distilled off for 3 times, the required quality (0.2% by weight or less of thionyl chloride) is not reached.

In the above Examples and Comparative Examples, the content ratios of the respective components were obtained as follows.

(1) ICC in reaction solution or concentrated residue:

The ICCC contained in the reaction solution or concentrated residue was derivatized to the corresponding ICC methyl ester by pretreating the reaction solution or concentrated residue. The pre-treated specimens were analyzed by HPLC (detection at UV 210 nm). The ICC content (ICC / ICCC%) was obtained by dividing the area of the detected ICC by the area of the ICC methyl ester.

(2) thionyl chloride in reaction solution or concentrated residue:

The thionyl chloride contained in the reaction solution or concentrated residue was derivatized with diethyl sulfite by pretreating the reaction solution or the concentrated residue. The pre-treated specimens were analyzed by GC. The content (% by weight) of thionyl chloride was obtained by quantifying diethyl sulfite detected using a standard product.

(3) ICCC in concentrated residue:

By reacting the concentrated residue with isobutylamine in the pretreatment, the ICCC was derivatized to the corresponding amide and the pre-treated sample was analyzed by HPLC (UV, detection at 210 nm). The content (% by weight) of ICCC was obtained by quantifying the detected amide using a standard product.

The results of Examples 1 and 2 and Comparative Examples 1 and 2 are summarized in Table 1.

Figure 112008068151665-pct00010

As the quality of ICCC, ICC is required to be not more than 2.0%, and thionyl chloride is required to be not more than 0.2% by weight. However, when the reaction is carried out without using DMI, ICC is left as a result of using 1.03eq of SOCl 2 , It can be seen from the results shown in Table 1 that the residual amount of thionyl chloride is increased by increasing the amount of SOCl 2 , and the desired ICCC of the desired quality can not be obtained quickly.

Example 3 (0.05% of 1,1,3,3-tetramethylurea)

0.015 g (0.05%) of 1,1,3,3-tetramethylurea was added to 30 g (176 mmol) of ICC and 21.6 g (182 mmol, 1.03 equivalent) of thionyl chloride was added dropwise at 40 ° C for 3 hours (ICC 7.8% residual). After the dropwise addition, the reaction was continued for 1 hour (ICC remained at 2.1%) while distilling off the dissolved acidic gas at 30 kPa and 40 ° C under reduced pressure. Further, distillation of thionyl chloride at 5 kPa and 40 DEG C was carried out for 3 hours to obtain 32.4 g of ICCC as a concentrated residue. The ICC remaining in the ICCC was 2.0%.

Example 4 (1, 3 -dimethylurea 0.05%)

0.016 g (0.05%) of DMI was added to 30 g (176 mmol) of ICC, and 21.6 g (182 mmol, 1.03 equivalent) of thionyl chloride was added dropwise at 40 캜 for 3 hours (ICC at the end of dropwise addition was 10.4%). After the dropwise addition, the reaction was continued for 1 hour (ICC remained 3.9%) while distilling off the dissolved acid gas at 30 kPa and 40 ° C under reduced pressure. Furthermore, by distilling off the thionyl chloride at 5 kPa and 40 占 폚 for 3 hours, 30.6 g of ICCC was obtained as a concentrated residue. The ICC remaining in the ICCC was 4.7%.

Example 5 (urea 0.05%)

0.016 g (0.05%) of DMI was added to 30 g (176 mmol) of ICC, and 21.6 g (182 mmol, 1.03 equivalent) of thionyl chloride was added dropwise at 40 占 폚 for 3 hours (ICC at the end of the drop was 16.3% remained). After the dropwise addition, the reaction was continued for 1 hour (ICC remained at 7.1%) while the dissolved acid gas was distilled off under reduced pressure at 30 kPa and 40 ° C. Furthermore, distillation of thionyl chloride at 5 kPa and 40 DEG C was carried out for 3 hours to obtain 31.7 g of ICCC as a concentrated residue. The ICC remaining in the ICCC was 6.6%, and thionyl chloride was less than 0.01% by weight.

The results of Examples 3 to 5 are summarized in Table 2.

Figure 112008068151665-pct00011

Compared with Comparative Example 1 in Table 1, it can be seen from the results of Table 2 that ICCC can be obtained quickly by using a specific urea compound.

Example 6

Manufacture of nateglinide

To 19.3 g of D-phenylalanine was added 143 ml of water and 77 ml of a 10% aqueous solution of potassium hydroxide to dissolve the solution. 82 ml of acetone was added thereto and the solution was cooled to about 10 캜. 20.0 g (purity: about 99%) of trans-4-isopropylcyclohexylcarbonyl chloride obtained in the same manner as in Example 2 was dropped thereinto, and the pH was adjusted to 13.5 to 14.0 with 10% aqueous potassium hydroxide solution The reaction was carried out while adjusting to obtain the target compound (trans-4-isopropylcyclohexylcarbonyl-D-phenylalanine).

Claims (12)

  1. Reacting a carboxylic acid compound of formula I with an acid chlorinating agent in the presence of a urea compound of formula II wherein 0.8 to 5 mol of an acid chlorinating agent is used per mole of the carboxylic acid compound of formula I and a catalytic amount of a urea compound of formula II Lt; RTI ID = 0.0 > (III) < / RTI >
    Formula I
    Figure 112013110703448-pct00012
    (II)
    Figure 112013110703448-pct00013
    (III)
    Figure 112013110703448-pct00014
    In the above formulas I, II and III,
    Ring A is a cyclohexane ring,
    R 1 is an alkyl group having 1 to 6 carbon atoms,
    R 2 and R 3 are independently hydrogen atom or an alkyl group having 1 to 3 carbon atoms each, by combining the R 5 and R 6 -R 5 -R 6 - to form, the art -R 5 -R 6 - is ethylene A trimethylene group or a tetramethylene group.
  2. The method of claim 1, wherein in formula II, R 2 and R 3 are both methyl group and, R 5 and R 6 are bonded to -R 5 -R 6 - art -R 5 -R 6 forms a, and - the Ethylene group.
  3. The process according to claim 1, wherein the reaction is carried out at room temperature to 80 ° C in the absence of solvent.
  4. 4. The process according to any one of claims 1 to 3, wherein the acid chloridating agent is thionyl chloride.
  5. A process for producing a D-phenylalanine derivative of the formula (V), which comprises reacting a D-phenylalanine compound of the formula (IV) with a carboxylic acid chloride compound of the formula (III) according to the production process according to claim 1.
    (III)
    Figure 112013110703448-pct00015
    Formula IV
    Figure 112013110703448-pct00016
    Formula V
    Figure 112013110703448-pct00017
    In the above formulas (III), (IV) and (V)
    Ring A is a cyclohexane ring,
    R 1 is an alkyl group having 1 to 6 carbon atoms,
    R 4 is a hydrogen atom, an alkyl group having 1 to 3 carbon atoms or a benzyl group.
  6. 6. The method according to claim 5, wherein R < 4 > is a hydrogen atom.
  7. A process for producing a D-phenylalanine derivative of the formula (V-2), which comprises the step of subjecting a D-phenylalanine derivative of the formula (V) wherein R 4 is an alkyl group having 1 to 3 carbon atoms or a benzyl group, .
    The compound of formula V-2
    Figure 112013110703448-pct00018
    In the above formula (V-2)
    Ring A is a cyclohexane ring,
    R 1 is an alkyl group having 1 to 6 carbon atoms.
  8. The production method according to any one of claims 1 to 3 and 5 to 7, wherein R 1 is a side chain alkyl group having 3 to 5 carbon atoms.
  9. delete
  10. delete
  11. delete
  12. delete
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6354321A (en) * 1985-03-27 1988-03-08 Ajinomoto Co Inc Blood sugar lowering agent
JPH01151529A (en) * 1987-11-05 1989-06-14 Soc Natl Poudres Explosifs Production of chloride of carboxylic acid
JPH0967299A (en) * 1995-06-20 1997-03-11 Mitsui Toatsu Chem Inc Production of acid halide
WO2002032853A1 (en) * 2000-10-18 2002-04-25 Ajinomoto Co.,Inc. Process for the preparation of acylphenylalanines

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2943432A1 (en) 1979-10-26 1981-05-21 Bayer Ag A process for the preparation of carboxylic acid halides
DE10199058I2 (en) * 1991-07-30 2006-04-27 Alcm Co Crystals of N- (trans-4-isopropylcyclohexylcarbonyl) -D-phenylalanine and process for their preparation
US5463116A (en) * 1991-07-30 1995-10-31 Ajinomoto Co., Inc. Crystals of N- (trans-4-isopropylcyclohexlycarbonyl)-D-phenylalanine and methods for preparing them
JPH0717899A (en) 1993-07-01 1995-01-20 Ajinomoto Co Inc Production of carboxylic acid chloride
US5750779A (en) 1995-06-20 1998-05-12 Mitsui Toatsu Chemicals, Inc. Preparation process of acyl halide or sulfonyl halide
EP1334963B1 (en) * 2000-10-18 2007-08-01 Ajinomoto Co., Inc. Process for producing nateglinide crystal
WO2004005240A1 (en) * 2002-07-03 2004-01-15 Teva Pharmaceutical Industries Ltd. Process for preparing nateglinide and intermediates thereof

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6354321A (en) * 1985-03-27 1988-03-08 Ajinomoto Co Inc Blood sugar lowering agent
JPH01151529A (en) * 1987-11-05 1989-06-14 Soc Natl Poudres Explosifs Production of chloride of carboxylic acid
JPH0967299A (en) * 1995-06-20 1997-03-11 Mitsui Toatsu Chem Inc Production of acid halide
WO2002032853A1 (en) * 2000-10-18 2002-04-25 Ajinomoto Co.,Inc. Process for the preparation of acylphenylalanines

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